Medical radionuclide imaging (e.g., nuclear medicine) is a key component of modern medical practice. This methodology involves the administration, typically by injection, of tracer amounts of a radioactive substance (e.g., radiotracer agents, radiotherapeutic agents, and radiopharmaceutical agents), which subsequently localize in the body in a manner dependent on the physiologic function of the organ or tissue system being studied. The radiotracer emissions, most commonly gamma photons, are imaged with a detector outside the body, creating a map of the radiotracer distribution within the body. When interpreted by an appropriately trained physician, these images provide information of great value in the clinical diagnosis and treatment of disease. Typical applications of this technology include detection of coronary artery disease (e.g., thallium scanning) and detection of cancerous involvement of bones (e.g., bone scanning). The overwhelming bulk of clinical radionuclide imaging is performed using gamma emitting radiotracers and detectors known as “gamma cameras”.
Recent advances in diagnostic imaging, such as magnetic resonance imaging (MRI), computerized tomography (CT), single photon emission computerized tomography (SPECT), and positron emission tomography (PET), have made a significant impact in cardiology, neurology, oncology, and radiology. Although these diagnostic methods employ different techniques and yield different types of anatomic and functional information, this information is often complementary in the diagnostic process.
Imaging agents are generally classified as either being diagnostic or therapeutic in their application. Although diagnostic imaging agents have historically been a mainstay in the nuclear pharmacy industry, during the past decade there has been increased interest in the development and use of radioactive imaging agents for radiotherapy. This shift in focus has been elicited primarily from research involving combining radioactive isotopes with sophisticated molecular carriers. Because of radiation's damaging effect on tissues, it is important to target the biodistribution of radiopharmaceuticals as accurately as possible. Generally speaking, PET uses imaging agents labeled with positron-emitters such as 18F, 11C, 13N, 15O, 75Br, 76Br, and 124I; SPECT uses imaging agents labeled with single-photon-emitters such as 201Tl, 99mTc, 123I, and 131I.
In the art, glucose-based and amino acid-based compounds have been used as imaging agents. Amino acid-based compounds are more useful in analyzing tumor cells due to their faster uptake and incorporation into protein synthesis. Of the amino acid-based compounds, 11C- and 18F-containing compounds have been used with success. 11C-containing radiolabeled amino acids suitable for imaging include, for example, L-[1-11C]leucine (Keen et al. J. Cereb. Blood Flow Metab. 1989 (9)429-45; herein incorporated by reference in its entirety), L-[1-11C]tyrosine (Wiesel et al. J. Nucl. Med. 1991 (32):2041-49; herein incorporated by reference in its entirety), L-[methyl-11C]methionine (Comar et al. Eur. J. Nucl. Med. 1976 (1):11-14; herein incorporated by reference in its entirety) and L-[1-11C]methionine (Bolster et al. Appl. Radiat. Isot. 1986 (37)1069-70; herein incorporated by reference in its entirety).
PET involves the detection of gamma rays in the form of annihilation photons from short-lived positron emitting radioactive isotopes including but not limited to 18F with a half-life of approximately 110 minutes, 11C with a half-life of approximately 20 minutes, 13N with a half-life of approximately 10 minutes, and 15O with a half-life of approximately 2 minutes, using the coincidence method.
For PET imaging studies of cardiac sympathetic innervation, carbon-11 (11C) labeled compounds such as [11C]meta-hydroxyephedrine (HED) are frequently used at major PET centers that have in-house cyclotrons and radiochemistry facilities. However, the nuclear medicine market has recently seen a substantial increase in stand-alone PET imaging centers that do not have cyclotrons and that primarily use 2-[18F]fluoro-2-deoxy-D-glucose (FDG) for PET imaging of cancerous tumors.
SPECT, on the other hand, uses longer-lived isotopes including but not limited to 99mTc with a half-life of approximately 6 hours and 201Tl with a half-life of approximately 74 hours. However, the resolution in present SPECT systems is lower than that presently available in PET systems.
Radio-iodinated meta-iodobenzylguanidine (MIBG) is a radiotracing agent that is used, for example, in nuclear medicine imaging studies of sympathetic nerve fibers in the human heart. Studies with MIBG allow clinicians to map the regional distribution of nerve fibers in the heart using imaging devices found in all nuclear medicine clinics. MIBG is also used for diagnostic imaging and radiotherapy of adrenergic tumors, such as neuroblastoma and pheochromocytoma.
New compounds that find use as imaging agents within nuclear medicine applications (e.g., PET imaging and SPECT imaging) have been described: for example, fluorine-18-labeled phenethylguanidines. See, e.g., U.S. Pat. No. 7,534,418, incorporated herein by reference in its entirety for all purposes.
While useful, introducing fluorine-18 into a phenyl ring moiety at high specific activities is a notoriously challenging radiolabeling task, especially in electron-rich aromatic systems. In the last 10 years, the use of diaryliodium salt precursors as a one-step method of introducing fluorine-18 into ring structures with high radiochemical yields has received considerable attention. Although this method has been used to prepare small model compounds with relatively simple structures, as the structures of the compounds being radiolabeled become more complex, radiochemical yields drop substantially. Accordingly, a need exists for methods of preparing fluorine-18 labeled phenethylguanidines and related compounds with high specific activity to make practical the production of such compounds on a commercial scale.